Landscape of Driver Gene Events, Biomarkers and Druggable Targets Identified by Whole Genome Sequencing of Glioblastomas

Background The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS. Methods Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs) and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes and potential targeted therapies. Results Tumor mutational burden (TMB) was similar to other WGS efforts (1-342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent non-coding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples. Conclusions With high quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients.

HR-MPF: high-resolution representation network with multi-scale progressive fusion for pulmonary nodule segmentation and classification

Accurate segmentation and classification of pulmonary nodules are of great significance to early detection and diagnosis of lung diseases, which can reduce the risk of developing lung cancer and improve patient survival rate. In this paper, we propose an effective network for pulmonary nodule segmentation and classification at one time based on adversarial training scheme. The segmentation network consists of a High-Resolution network with Multi-scale Progressive Fusion (HR-MPF) and a proposed Progressive Decoding Module (PDM) recovering final pixel-wise prediction results. Specifically, the proposed HR-MPF firstly incorporates boosted module to High-Resolution Network (HRNet) in a progressive feature fusion manner. In this case, feature communication is augmented among all levels in this high-resolution network. Then, downstream classification module would identify benign and malignant pulmonary nodules based on feature map from PDM. In the adversarial training scheme, a discriminator is set to optimize HR-MPF and PDM through back propagation. Meanwhile, a reasonably designed multi-task loss function optimizes performance of segmentation and classification overall. To improve the accuracy of boundary prediction crucial to nodule segmentation, a boundary consistency constraint is designed and incorporated in the segmentation loss function. Experiments on publicly available LUNA16 dataset show that the framework outperforms relevant advanced methods in quantitative evaluation and visual perception.

Advances in magnetic resonance imaging contrast agents for glioblastoma-targeting theranostics

Glioblastoma (GBM) is the most aggressive malignant brain tumour, with a median survival of 3 months without treatment and 15 months with treatment. Early GBM diagnosis can significantly improve patient survival due to early treatment and management procedures. Magnetic resonance imaging (MRI) using contrast agents is the preferred method for the preoperative detection of GBM tumours. However, commercially available clinical contrast agents do not accurately distinguish between GBM, surrounding normal tissue, and other cancer types due to their limited ability to cross the blood-brain barrier (BBB), their low relaxivity, and their potential toxicity. New GBM-specific contrast agents are urgently needed to overcome the limitations of current contrast agents. Recent advances in nanotechnology have produced alternative GBM-targeting contrast agents. The surfaces of nanoparticles (NPs) can be modified with multimodal contrast imaging agents and ligands that can specifically enhance the accumulation of NPs at GBM sites. Using advanced imaging technology, multimodal NP-based contrast agents have been used to obtain accurate GBM diagnoses in addition to an increased amount of clinical diagnostic information. NPs can also serve as drug delivery systems for GBM treatments. This review focuses on the research progress for GBM-targeting MRI contrast agents as well as MRI-guided GBM therapy.

Longitudinal effects of modified creatinine index on all-cause mortality in individuals receiving hemodialysis treatment

BACKGROUND: The modified creatinine index (mCI), as a surrogate marker of muscle mass, has been associated with poor outcomes in patients undergoing hemodialysis. However, a single assessment may not reflect the clinical significance before an adverse clinical endpoint. OBJECTIVE: Analyze mCI trajectories and their association with all-cause mortality in incident hemodialysis patients. DESIGN: Retrospective observational cohort. SETTING: Outpatient dialysis facility. PATIENTS AND METHODS: We followed a cohort of patients who underwent maintenance hemodialysis treatment at least three times weekly for at least three months from 19 June 2010 to 29 December 2017. Clinical and laboratory features were measured at baseline. Longitudinal changes in the mCI were modeled using a joint longitudinal and survival model adjusted for baseline covariates and body mass index trajectories. MAIN OUTCOME MEASURE: All-cause mortality. SAMPLE SIZE: 408 with 208 males (50.7%). RESULTS: The mean (SD) age was 62.2 (12.3) years. The mCI changes were evaluated for a median (interquartile range) follow-up of 2.16 (1.13, 3.73) years. Forty-six percent (n=188) of patients reached the endpoint. A steeper slope (per 0.1 unit increase in the decrease rate) in modified creatinine index was associated with increased risk of all-cause mortality (HR, 1.04; 95% CI, 1.02–1.07; P =.011). In addition, an annual 1 mg/kg/day decrease in modified creatinine index level increased the hazard of all-cause mortality by 4% (HR, 1.04; 95% CI, 1.02–1.07; P =.001). LIMITATIONS: Residual kidney function was not observed in the data. Setting was single center and thus results may not be generalizable to other populations. CONCLUSION: All-cause death was significantly associated with loss of muscle mass over time. Longitudinal trajectories of nutritional markers may predict the clinical outcomes in patients undergoing hemodialysis. This may also be valuable for individual risk stratification. Furthermore, early management may provide an opportunity to improve patient survival. CONFLICT OF INTEREST: None.

The Effects of a Ketogenic Diet on Patients with Dihydrolipoamide Dehydrogenase Deficiency

Background: Dihydrolipoamide dehydrogenase (DLD lipoamide dehydrogenase, the E3 subunit of the pyruvate dehydrogenase complex (PDHC)) is the third catalytic enzyme of the PDHC, which converts pyruvate to acetyl-CoA catalyzed with the introduction of acetyl-CoA to the tricyclic acid (TCA) cycle. In humans, PDHC plays an important role in maintaining glycose homeostasis in an aerobic, energy-generating process. Inherited DLD-E3 deficiency, caused by the pathogenic variants in DLD¸ leads to variable presentations and courses of illness, ranging from myopathy, recurrent episodes of liver disease and vomiting, to Leigh disease and early death. Currently, there is no consensus on treatment guidelines, although one suggested solution is a ketogenic diet (KD). Objective: To describe the use and effects of KD in patients with DLD-E3 deficiency, compared to the standard treatment. Results: Sixteen patients were included. Of these, eight were from a historical cohort, and of the other eight, four were on a partial KD. All patients were homozygous for the D479V (or D444V, which corresponds to the mutated mature protein without the mitochondrial targeting sequence) pathogenic variant in DLD. The treatment with partial KD was found to improve patient survival. However, compared to a historical cohort, the patients’ quality of life (QOL) was not significantly improved. Conclusions: The use of KD offers an advantage regarding survival; however, there is no significant improvement in QOL.

Challenges and Prospects for Designer T and NK Cells in Glioblastoma Immunotherapy

Glioblastoma (GBM) is the most prevalent, aggressive primary brain tumour with a dismal prognosis. Treatment at diagnosis has limited efficacy and there is no standardised treatment at recurrence. New, personalised treatment options are under investigation, although challenges persist for heterogenous tumours such as GBM. Gene editing technologies are a game changer, enabling design of novel molecular-immunological treatments to be used in combination with chemoradiation, to achieve long lasting survival benefits for patients. Here, we review the literature on how cutting-edge molecular gene editing technologies can be applied to known and emerging tumour-associated antigens to enhance chimeric antigen receptor T and NK cell therapies for GBM. A tight balance of limiting neurotoxicity, avoiding tumour antigen loss and therapy resistance, while simultaneously promoting long-term persistence of the adoptively transferred cells must be maintained to significantly improve patient survival. We discuss the opportunities and challenges posed by the brain contexture to the administration of the treatments and achieving sustained clinical responses.

Measuring the Metabolic Evolution of Glioblastoma throughout Tumor Development, Regression, and Recurrence with Hyperpolarized Magnetic Resonance

Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma can improve patient survival by providing physicians the time to optimally deliver treatment. This research tested whether metabolic imaging with hyperpolarized MRI could detect changes in tumor progression faster than conventional anatomic MRI in patient-derived glioblastoma murine models. To capture the dynamic nature of cancer metabolism, hyperpolarized MRI, NMR spectroscopy, and immunohistochemistry were performed at several time-points during tumor development, regression, and recurrence. Hyperpolarized MRI detected significant changes of metabolism throughout tumor progression whereas conventional MRI was less sensitive. This was accompanied by aberrations in amino acid and phospholipid lipid metabolism and MCT1 expression. Hyperpolarized MRI can help address clinical challenges such as identifying malignant disease prior to aggressive growth, differentiating pseudoprogression from true progression, and predicting relapse. The individual evolution of these metabolic assays as well as their correlations with one another provides context for further academic research.

Transplant Oncology: An Evolving Field in Cancer Care

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The application of oncology, transplant medicine, and surgery to improve patients’ survival and quality of life is the core of transplant oncology. Hepatobiliary malignancies have been treated by liver transplantation (LT) with significant improved outcome. In addition, as the liver is the most common site of metastasis for colorectal cancer (CRC), patients with CRC who have stable unresectable liver metastases are good candidates for LT, and initial studies have shown improved survival compared to palliative systemic therapy. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years in a stepwise manner; however, they have only been shown to improve patient survival in the setting of limited systemic therapy options. This review illustrates the concept and history of transplant oncology as an evolving field for the management of hepatocellular carcinoma, intrahepatic biliary cancer, and liver-only metastasis of non-hepatobiliary carcinoma. The utility of immunotherapy in the transplant setting is discussed as well as the feasibility of using circulating tumor DNA for surveillance post-transplantation.

High Flow Nasal Cannula Oxygen In Non-Critical Care Units In Patients Infected With SARS-CoV-2 Who Are Not Suitable For Intensive Care Unit

Background:High-flow nasal cannula (HFNC) is a recent respiratory support technique used for patients with hypoxemic respiratory failure; its use usually takes place in critical care wards. During the second wave of Covid-19, almost 400 000 people were hospitalized in France, and intensive care units were overwhelmed. For patients who did not meet criteria for admission to an intensive care unit because of their age or their medical background, we proposed HFNC in non-critical care unit instead of standard oxygen therapy to improve patient survival and comfort.Objectives: To describe characteristics and outcomes of patients infected with SARS-CoV-2 with HFNC in non-critical care wards between September 2020 and June 2021.Methods: This was a single-center, retrospective cohort study conducted between September and June 2021 in Clamart Hospital, France. Patients infected with SARS-CoV-2 confirmed, who were not suitable for intensive care unit escalation, and who were proposed HFNC because of respiratory failure were assessed.Results:Thirty-one patients with SARS-CoV-2 were included, median age 87.0 years (interquartile range (IQR), 82.0-91.0), 52% men. Nineteen (61%) patients were OMS score 0, i.e. no disability in daily-life activities. HNFC was started a median of 3 days (IQR, 1-5.5) after hospitalization. Overall, median duration of HNFC was 6 days (IQR, 4-10). Eleven patients (35.5%) survived and were discharged from hospital.Conclusions:Our experience of HFNC for patients with COVID-19 outside of a critical care environment because of their age and comorbidities is positive allowing survival of 35% of old patients not admitted to an intensive care unit. Trial registration:Not applicable

Sporadic Burkitt Lymphoma Presenting with Middle Cranial Fossa Masses with Sphenoid Bony Invasion and Acute Pancreatitis in a Child

Acute pancreatitis in children is usually due to infection, trauma, or anatomical abnormalities and is rarely due to obstruction from malignancy. Sporadic Burkitt lymphoma (BL) is an aggressive non-Hodgkin B-cell lymphoma that usually involves the bowel or pelvis, with isolated cases presenting as acute pancreatitis. We report a case of BL in a 12-year-old male presenting as acute pancreatitis with obstructive jaundice and a right middle cranial fossa mass invading the sphenoid bone. The common bile duct in this case was dilated to 21 mm in diameter on abdominal ultrasound and to 26 mm on magnetic resonance cholangiopancreatography (MRCP), significantly greater than any value reported in the literature for BL. Given the rapidly progressing nature of BL, we emphasize the importance of recognizing heterogeneous presentations of this disease to improve patient survival. We also conclude that it is important to consider malignancy in a child with acute pancreatitis, particularly in the presence of obstructive jaundice or multisystem involvement. Other Presentations. This case report has no prior publications apart from the abstract being accepted to the 2020 SIOP (International Society of Pediatric Oncology) meeting and 2020 ASPHO conference (canceled due to the COVID-19 pandemic) and subsequently published as an abstract only in Pediatric Blood and Cancer. We have also presented the abstract as a poster presentation at our institution’s (NYU Langone Hospital—Long Island, previously known as NYU Winthrop) annual research day conference in 2020.